CD40 is a member of the TNF receptor superfamily that is expressed on a wide variety of cells including antigen presenting cells (e.g., dendritic cells, macrophages, B cells) and non-immune cells, such as endothelial cells, smooth muscle cells, fibroblasts, epithelial cells, astrocytes and neurons. Its counter-receptor, CD154 (CD40 ligand), is expressed primarily on activated CD4+ T cells; although, other cells, such as platelets can also express CD154.
The interaction between CD40 and CD154 is central to the pathogenesis of numerous diseases including, for example, atherosclerosis, neurodegenerative disorders (e.g., Alzheimer's disease, cerebral ischemia, multiple sclerosis, amyotrophic lateral sclerosis) various autoimmune disorders (e.g., inflammatory bowel disease, systemic lupus erythematosus, rheumatoid arthritis, graft rejection, idiopathic thrombocytopenic purpura, inflammatory myopathies, etc.), rejection of transplanted organs, and ischemia. Numerous studies have demonstrated that in vivo blockade of the CD40-CD154 pathway controls these diseases in animals. Another role of CD40-CD154 interaction is to activate mechanisms of resistance against a broad variety of pathogens. This is important because approaches to control CD40-mediated diseases should ideally manipulate this pathway so that mechanisms of host resistance remain largely intact.
The relevance of CD40-CD154 interaction in the pathogenesis of numerous diseases has led to clinical trials which examined the effects of blocking this pathway. While generalized blockade of CD40 signaling by administration of an anti-CD154 monoclonal antibody appeared effective, the studies were discontinued because anti-CD154 monoclonal antibodies caused platelet aggregation and thrombosis. These effects are likely caused by activation of platelets via engagement of CD154 expressed on their membrane. Thus, approaches to target CD40 for therapy have not been feasible, and indiscriminate inhibition of the CD40 pathway may cause susceptibility to opportunistic infections.